Rescuing the cytolytic function of APDS1 patient T cells via TALEN-mediated PIK3CD gene correction,Molecular Therapy - Methods & Clinical Development

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Rescuing the cytolytic function of APDS1 patient T cells via TALEN-mediated PIK3CD gene correction
Molecular Therapy - Methods & Clinical Development ( IF 4.6 ) Pub Date : 2023-10-10 , DOI: 10.1016/j.omtm.2023.101133
Lucie Poggi _{1,

2} , Loïc Chentout _{1,

2} , Sabrina Lizot ₃ , Alex Boyne ₄ , Alexandre Juillerat ₄ , Arianna Moiani ₃ , Marine Luka _{5,

6} , Francesco Carbone _{5,

6} , Mickael Ménager _{5,

6} , Marina Cavazzana _{1,

7} , Philippe Duchateau ₄ , Julien Valton ₃ , Sven Kracker _{1,

2}

Affiliation

Gain-of-function mutations in the gene result in activated phosphoinositide 3-kinase δ syndrome type 1 (APDS1). This syndrome is a life-threatening combined immunodeficiency and today there are neither optimal nor long-term therapeutic solutions for APDS1 patients. Thus, new alternative treatments are highly needed. The aim of the present study is to explore one therapeutic avenue that consists of the correction of the gene through gene editing. Our proof-of-concept shows that TALEN-mediated gene correction of the mutated gene in APDS1 T cells results in normalized phospho-AKT levels in basal and activated conditions. Normalization of PI3K signaling was correlated to restored cytotoxic functions of edited CD8+ T cells. At the transcriptomic level, single-cell RNA sequencing revealed corrected signatures of CD8+ effector memory and CD8+ proliferating T cells. This proof-of-concept study paves the way for the future development of a gene therapy candidate to cure activated phosphoinositide 3-kinase δ syndrome type 1.

中文翻译：

通过 TALEN 介导的 PIK3CD 基因校正挽救 APDS1 患者 T 细胞的溶细胞功能

该基因的功能获得性突变会导致磷酸肌醇 3-激酶 δ 综合征 1 型 (APDS1) 激活。这种综合征是一种危及生命的联合免疫缺陷病，目前对于 APDS1 患者既没有最佳的治疗方案也没有长期的治疗方案。因此，非常需要新的替代疗法。本研究的目的是探索一种通过基因编辑纠正基因的治疗途径。我们的概念验证表明，TALEN 介导的 APDS1 T 细胞突变基因的基因校正可导致基础条件和激活条件下的磷酸 AKT 水平标准化。 PI3K 信号传导的正常化与编辑的 CD8+ T 细胞的细胞毒功能的恢复相关。在转录组水平上，单细胞 RNA 测序揭示了 CD8+ 效应记忆和 CD8+ 增殖 T 细胞的正确特征。这项概念验证研究为未来开发治疗 1 型活化磷酸肌醇 3-激酶 δ 综合征的基因疗法候选药物铺平了道路。

更新日期：2023-10-10

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